Beyond the Lens: Impact of Intravitreal anti-Neovascular agents on Kidney outcomes in Diabetic patients with Chronic Kidney Disease (BLINK-CKD): A retrospective observational cohort study

Diabetic kidney disease is rising in prevalence and is the leading cause of chronic kidney disease (CKD) worldwide. Along with the diabetic complications of nephropathy, retinal complications of diabetes are also on the rise. Approximately one-third of diabetic patients have retinopathy at presentation. Diabetic retinal complications can range from non-proliferative retinopathy (NPDR) to proliferative diabetic retinopathy (PDR) and diabetic macular edema (DME). The treatment of diabetic retinopathy has been revolutionized in the recent years with the rise of the Intra-vitreal (IVT) Anti-vascular-endothelial-growth-factor (Anti-VEGF) agents, particularly in the use of DME.  

The systemic use of Anti-VEGF agents in oncological cases is known to cause nephrotoxicity, and patients are usually counselled on renal adverse effects of systemic anti-VEGF therapy prior to initiation. However, the renal effects of IVT anti-VEGF agents are less studied and data on how they affect kidney function is not well established.  

Our study’s aim to analyse the kidney outcomes of diabetic CKD patients (eGFR < 60ml/min) treated with IVT Anti-VEGF. Patients with established diabetic retinopathy are already at higher risk of worse kidney outcomes. In this patient group, does the use of IVT Anti- VEGF agents further accelerate the progression of kidney disease? Or does this only happen in a subgroup of patients with advanced kidney disease or heavy proteinuria? Answering these questions will allow for appropriate counselling, monitoring of renal function and selection of treatment for diabetic retinopathy in the hopes to delay progression to end stage kidney failure. 

This is a single-centre retrospective, observational cohort study of patients with diabetic kidney disease and diabetic retinopathy. We analysed the trend of eGFR changes in these patients who were treated with IVT anti-VEGF agents compared to a control group who have not been exposed to IVT Anti-VEGF agents. Secondary outcomes included proteinuria trend, time to renal replacement therapy (RRT), time to eGFR <10ml/min and greater than 30% decline from baseline eGFR. 

We identified patients who were seen at Ophthalmology clinic between 01/01/2022 till 30/06/2025.  A list of patients with the diagnostic code of diabetic retinopathy, proliferative diabetic retinopathy, non-proliferative diabetic nephropathy, and diabetic macula edema were identified. Patients with a baseline renal function of eGFR 10 to 60ml/min were included in the study. Existing patients on renal replacement therapy and renal transplant patients were excluded from the study. To be included in the study, patients must have had regular renal function blood test (at least 2 readings of eGFR a year) during study data collection period. Patients who newly received at least 3 doses of Anti-VEGF treatment within a 6-month period were included in the exposure group. Patients who were given 1-2 doses of IVT Anti-VEGF injections were excluded from the study. The comparator group includes patients who were not treated with any IVT Anti-VEGF inhibitors during the study period.  

Study Variables 

Baseline characteristics were summarized for the study population, comparator group and subgroups based on the stage of CKD and IVT Anti-VEGF inhibitor usage. These were expressed as means (± standard deviations) or numbers (percentages). Differences between the groups were compared using independent Student’s t-tests and χ2-tests for normally distributed continuous and categorical variables, respectively. Non-parametric data were compared using the Mann–Whitney U test.  

Renal function was assessed by eGFR. We used the Kidney Disease: Improving Global Outcomes (KDIGO) classification to classify renal function (G1, G2, G3a, G3b, G4, and G5). We will register if there was renal eGFR worsening and compared the slope of eGFR decline between study and comparator groups.  

Patients who reached end stage kidney disease and started on renal replacement therapy (RRT) including haemodialysis, peritoneal dialysis during study period were recorded. 

Baseline Characteristics 

A total of 1262 patients were included in the study (Table 1). All were diabetic patients with eGFR between 10 to 60ml/min. The mean duration of follow-up was 21.2 months. 213 patients were treated with IVT Anti-VEGF (minimum 3 injections over a 6-month period). The comparator group included 1049 patients who were not exposed to IVT Anti-VEGF. 

Trend of EGFR decline 

Patients treated with IVT Anti-VEGF showed significantly faster eGFR decline per visit (-0.80 vs -0.51 mL/min/1.73m² per visit, p < 0.001). Anti-VEGF patients showed larger percentage decreases from baseline (median -9.1% vs -3.1%, p < 0.001). In addition, Anti-VEGF treated patients had a significantly higher proportion experiencing severe kidney function decline, with 36.6% versus 23.3% of untreated patients showing >30% eGFR reduction from baseline (p < 0.001). The number of patients who reached eGFR<10ml/min or started on RRT after exposure to IVT Anti-VEGF treatment was significantly higher (17.8% versus 7.8%, p < 0.001). Despite similar baseline eGFR, Anti-VEGF treatment was associated with significantly worse renal function deterioration across all parameters. 

Table 3. Comparison of renal function (eGFR) in patients between treated with IVT Anti-VEGF therapy and no IVT Anti-VEGF therapy groups 

 1. Linear mixed-effects model was performed 

1.1 Baseline eGFR Baseline eGFR 

No significant difference in baseline eGFR between treatment groups (p = 0.369) 

1.2 eGFR slope (mL/min/1.73m² per visit) 

Exposure to IVT Anti-VEGF group showed significantly faster eGFR decline per visit compared to control group with no Anti-VEGF treatment (p < 0.001) 

2. Mann-Whitney U test was performed 

Percentage change from baseline (%) 

IVT Anti-VEGF group showed significantly greater percentage eGFR decline from baseline compared to no Anti-VEGF group (p < 0.001) 

3. Chi-square test was performed 

IVT Anti-VEGF group had significantly higher proportion of patients with severe eGFR decline (>30%) compared to no Anti-VEGF group (p < 0.001) 

Despite similar baseline eGFR, patients receiving IVT Anti-VEGF treatment showed significantly worse renal function deterioration across all parameters. 

Trend of proteinuria

Patients treated with Anti-VEGF had significantly higher baseline UPCR values compared to untreated patients (373.2 vs 218.2 mg/mmol, p < 0.001). Treated with Anti-VEGF group showed significantly faster absolute deterioration in UPCR per visit compared to No treatment with Anti-VEGF (20.3 vs 7.2 mg/mmol per visit, p = 0.016). There was no significant difference in percentage UPCR change between Treated with Anti-VEGF group and No treatment with Anti-VEGF (median 0% for both groups, p = 0.911). These findings suggest that whilst treated with Anti-VEGF patients showed more severe baseline proteinuria, Anti-VEGF treatment was associated with a faster rate of proteinuria progression over time, though the overall endpoint comparison showed no significant difference between groups. 

Table 4. Comparison of renal function (UPCR) in patients between treated with IVT Anti-VEGF therapy and no IVT Anti-VEGF therapy groups 

1. Linear mixed effects model was performed. 

1.1. Baseline UPCR (mg/mmol) 

Patients treated with IVT anti-VEGF had significantly higher baseline UPCR values compared to untreated patients (373.2 vs 218.2 mg/mmol, p < 0.001). 

1.2 UPCR slope (mg/mmol per visit) 

IVT Anti-VEGF treated patients showed significantly faster absolute deterioration in UPCR compared to untreated patients (20.3 vs 7.2 mg/mmol per visit, p = 0.016). 

2. Mann-Whitney U test was performed 

UPCR percentage change from baseline (%) 

There was no significant difference in percentage UPCR change from baseline between IVT Anti-VEGF treated and No treatment with Anti-VEGF (p = 0.911) 

The use of IVT Anti-VEGF agents was thought to be limited to retinal effects only, and systemic absorption of these medications was assumed to be minimal. However, our study demonstrates that there is a trend to worsening renal outcomes in diabetic kidney disease patients who have been exposed to IVT Anti-VEGF treatment. Degree of proteinuria increases, eGFR decline is more rapid, with more proportion of patients reaching eGFR <10ml/min and starting on renal replacement therapy. Our study findings prompt further research into the renal effects of IVT Anti-VEGF treatment. Patients with established CKD should have close monitoring of their renal function while on treatment with IVT Anti-VEGF agents, with the aim to consider switching to alterative treatment options if there are concerns of rapidly worsening renal function without other contributing causes.